In a 36-year-old patient with recurrent fevers >101 °F, elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), normal chest radiograph, normal laboratory studies, negative blood cultures, and an unremarkable physical examination, what is the most likely diagnosis?

Fever of Unknown Origin (FUO) with Elevated Inflammatory Markers

This patient meets the classic definition of Fever of Unknown Origin (FUO), and the most appropriate next step is to obtain an [¹⁸F]FDG PET/CT scan to identify the underlying etiology, which has an 84% sensitivity and 76% diagnostic accuracy in this clinical scenario 1.

Diagnostic Classification

This 36-year-old patient fulfills the formal criteria for FUO, defined as:

• Fever >38.3°C (100.9°F)
• Duration >3 weeks
• No diagnosis despite appropriate initial workup (3 outpatient visits or inpatient days) 1

The elevated CRP and ESR confirm this is Inflammation of Unknown Origin (IUO) when combined with FUO, which shares similar etiologies including infectious, inflammatory, malignant, and miscellaneous causes 1.

Recommended Diagnostic Approach

Immediate Next Step: Advanced Imaging

Order [¹⁸F]FDG PET/CT as the next diagnostic test 1. This imaging modality demonstrates:

• Sensitivity: 84-86% for detecting FUO/IUO causes
• Specificity: 62-63%
• Diagnostic yield: 56% (meaning it identifies the cause in over half of cases)
• Helpfulness: 61% in guiding further management
• Cost-effective when performed early in the diagnostic workup 1

The PET/CT should ideally be performed within 3 days if glucocorticoid therapy is being considered, as steroids can reduce diagnostic yield 1.

Differential Diagnosis Framework

Based on the elevated inflammatory markers (CRP and ESR) without identified source, consider these categories in order of likelihood:

1. Inflammatory/Rheumatologic Diseases (Most Common in This Age Group)

• Adult-Onset Still's Disease (AOSD) - particularly likely given:
  • Recurrent spiking fevers
  • Elevated inflammatory markers (ESR/CRP)
  • Age 36 (can occur at any age despite the name)
  • Negative infectious workup 2, 3

AOSD classically presents with four major features: spiking fever, rash, arthralgia/arthritis, and high inflammation markers. However, not all features need be present initially 2. Look specifically for:

• Salmon-pink evanescent rash (may be subtle or absent)
• Joint symptoms (may be minimal early)
• Markedly elevated ferritin (should be checked if not already done)
• Sore throat
• Hepatosplenomegaly or lymphadenopathy

2. Occult Infection

• Despite negative cultures, consider:
  • Endocarditis (especially if any cardiac murmur present) 4
  • Spinal infection/epidural abscess (if any back pain) 5
  • Atypical organisms (Nocardia, fungi, mycobacteria) 6

3. Malignancy

• Lymphoma
• Solid tumors with paraneoplastic fever
• Note: CRP levels >100 mg/L should raise suspicion for malignancy or infection over pure inflammatory disease 7

4. Miscellaneous Causes

Critical Pitfalls to Avoid

Common Diagnostic Errors:

1. Assuming normal blood cultures exclude endocarditis - Culture-negative endocarditis occurs in 10-15% of cases. If any cardiac findings present, echocardiography (TTE followed by TEE if negative) is mandatory 4.

2. Overlooking spinal infection - Epidural abscess can present with fever alone before neurologic symptoms develop. Any history of back pain, IV drug use, diabetes, or recent procedures warrants spinal MRI 5.

3. Dismissing AOSD due to age - While called "adult-onset," it can occur at any adult age. The diagnosis is clinical and requires exclusion of infection and malignancy first 2, 3.

4. Misinterpreting isolated elevated inflammatory markers - In patients with elevated ESR/CRP and nonspecific findings, new-onset rheumatic disease accounts for 52.3% of cases, with polymyalgia rheumatica and seronegative arthritis being most common 7.

5. Starting empiric steroids prematurely - While steroids may improve symptoms temporarily (as seen in this patient's recurrent presentations), they can mask underlying infection or malignancy and reduce PET/CT diagnostic yield 1, 3.

Specific Additional Testing to Order Now

Beyond PET/CT, obtain:

• Ferritin level (markedly elevated >1000 ng/mL suggests AOSD) 2, 3
• Procalcitonin (helps differentiate bacterial infection from inflammatory disease)
• Echocardiography (TTE at minimum) given recurrent fever 4
• Age-appropriate cancer screening if not current
• Consider bone marrow biopsy if PET/CT shows marrow uptake

Prognostic Information

A negative PET/CT predicts favorable prognosis with potential for spontaneous remission, allowing a watchful waiting approach rather than empiric immunosuppression 1. This is clinically valuable information that can prevent unnecessary treatment.

Management Strategy Based on PET/CT Results

• If PET/CT identifies a focus: Proceed with targeted biopsy or specific treatment
• If PET/CT is negative: Consider empiric trial of IL-1 or IL-6 inhibitor for presumed AOSD after infectious/malignant causes definitively excluded 2, 3
• If PET/CT shows diffuse uptake: Strongly suggests systemic inflammatory disease; proceed with rheumatologic evaluation

The key principle: Do not start immunosuppressive therapy until infection and malignancy are reasonably excluded through advanced imaging and targeted biopsies as indicated 1, 2.